Christoph Nerl

Autologous Stem-Cell Transplantation As First-Line Therapy in Peripheral T-Cell Lymphomas: Results of a Prospective Multicenter Study

PURPOSE Peripheral T-cell lymphomas (PTCLs) are rare malignancies with poor outcome after conventional chemotherapy. The role of myeloablative therapy and autologous stem-cell transplantation (autoSCT) is still unclear. Therefore, we initiated the first prospective multicenter study on upfront autoSCT in PTCL and recently reported good feasibility and efficacy of this approach. Here, we present the final analysis of the study. PATIENTS AND METHODS The treatment regimen consisted of four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by mobilizing therapy with either the dexamethasone, carmustine, melphalan, etoposide, and cytarabine protocol or the etoposide, methylprednisolone, cytarabine, and cisplatin protocol and stem-cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemoradiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and autoSCT. RESULTS From June 2000 to April 2006, 83 patients were enrolled onto the study. Main subgroups were PTCL not specified (n = 32) and angioimmunoblastic T-cell lymphoma (n = 27). Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the overall response rate after myeloablative therapy was 66% (56% CR and 8% PR). With a median follow-up time of 33 months, 43 patients are alive; the estimated 3-year overall and disease-free survival rates for patients in CR (calculated from CR to the date of relapse) and 3-year progression-free survival rate were 48%, 53%, and 36%, respectively. CONCLUSION The results of this prospective study suggest a substantial impact on outcome for upfront autoSCT in PTCL and should be further evaluated in randomized trials. Pretransplantation treatment needs to be improved to increase the transplantation rate.

Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B‐cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m2 in a 30‐min IV infusion, d 1–3, and cyclophosphamide 250 mg/m2 in a 30‐min IV infusion on d 1–3. Cycles were repeated every 28 d. Twenty‐one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute‐sponsored Working Group, were recorded in 29 out of 32 assessable patients (90·6%). Twenty‐four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69·4%, 16·7% and 16·7%) respectively. Other side‐effects were uncommon. No treatment‐related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side‐effect. These results warrant further study on the FC combination in randomized trials.

Intensive consolidation versus oral maintenance therapy in patients 61 years or older with acute myeloid leukemia in first remission: results of second randomization of the AML HD98-B treatment trial

Intensive consolidation versus oral maintenance therapy in patients 61 years or older with acute myeloid leukemia in first remission: results of second randomization of the AML HD98-B treatment Trial

B‐cell chronic lymphocytic leukaemia cells express and release transforming growth factor‐β

Summary Transforming growth factor‐β (TGF‐β) has been described as a potent inhibitor of various cell types, among others of primitive haematopoietic progenitors in vitro, and as a negative autocrine regulator of normal B lymphocyte growth and differentiation. In the present study we investigated TGF‐β gene expression in peripheral blood mononuclear cells (PBMC) and in B cells from patients with B‐cell chronic lymphocytic leukaemia (B‐CLL) and from normal controls. Monocyte depleted B‐CLL cells expressed constitutively mRNA for TGF‐β1 and secreted low amounts of TGF‐β activity into the culture medium. Stimulation of cells by phorbol ester noticeably enhanced mRNA levels as well as protein secretion in most cases. TGF‐β activity was of the same magnitude as in normal controls. We next analysed TGF‐β in highly enriched B lymphocytes from B‐CLL (95100% CD19+), and found that TGF‐β secretion was up to 3 times higher than in the original PBMC population. It is discussed that B‐CLL cells might escape from negative regulation by TGF‐β and, on the other hand, inhibit normal haematopoietic cell proliferation and thereby achieve a growth advantage in the haematopoietic tissues.

Serum levels of soluble CD23, but not soluble CD25, predict disease progression in early stage B-cell chronic lymphocytic leukemia.

Serum levels of the soluble forms of CD23 (sCD23) and CD25 (sCD25) were prospectively analyzed with respect to their prognostic relevance in early stage B-cell chronic lymphocytic leukemia (B-CLL). SCD23 and sCD25 levels were determined in 105 patients with newly diagnosed B-CLL (Binet stage A). In 93 of the patients, these levels were correlated with other already established indicators for risk of disease progression, including the histologic pattern of bone marrow infiltration, lymphocyte doubling time (LDT), and the serum level of thymidine kinase (TK). High serum levels of both sCD23 and of sCD25 were associated with a diffuse bone marrow infiltration, a LDT < or = 12 months, and elevated (>5 U/L) serum TK, respectively. Moreover, examination of the clinical course of 76 untreated patients showed that high levels of sCD23, but not of sCD25, at initial diagnosis were linked with disease progression. Furthermore, in a stepwise Cox regression model, high levels of sCD23 and a short LDT were shown to be strong predictors of progressive disease within the first year of disease presentation. Therefore, it appears to be justified to incorporate sCD23 levels into the risk profile of early stage B-CLL and to take them into account for stratification in risk-adapted treatment strategies.

Peripheral T-cell non-Hodgkin's lymphomas of low malignancy: prospective study of 25 patients with pleomorphic small cell lymphoma, lymphoepitheloid cell (Lennert's) lymphoma and T-zone lymphoma

Peripheral T‐cell lymphomas comprise a heterogenous group of low‐ and high‐grade malignancies differing in their histopathological appearance and also in clinical and prognostic aspects. We prospectively studied 25 patients with low‐grade peripheral T‐cell lymphomas: pleomorphic, small cell lymphoma (PSC) (n = 9), lymphoepitheloid (Lennerts) lymphoma (LEL) (n= 12) and T‐zone lymphoma (TZL) (n= 4). The median patient age was 55 years (range 19‐75 years); the male to female ratio was 1.5. 13 patients (52%) had limited stages (I + II), 12 patients (48%) had advanced disease (stage III + IV). 21 patients received the COPBLAM/IMVP‐16 regimen. Two patients received more intensive treatments; two received less intensive therapy. Complete remissions were achieved in 16/25 patients (64%). The median observation time of surviving patients was 30 months (range 5‐72 months). The actuarial overall survival and event‐free survival at 2 years of 21 patients receiving COPBLAM/IMVP‐16 were 69% and 35%, respectively. Intensive chemotherapy led to complete remissions in about 60% of the patients and to long‐term disease‐free survival for one‐third. The observed clinical courses illustrate the aggressive nature of PSC, LEL and TZL.

HIV-RELATED NON-HODGKIN'S LYMPHOMA : CHOP INDUCTION THERAPY AND INTERFERON-ALPHA -2B/ZIDOVUDINE MAINTENANCE THERAPY

In a prospective multicenter study 68 out of 158 patients with HIV infection and malignant lymphoma were assigned to a risk-adapted induction therapy using the following algorithm: High-risk patients fulfilled 2 of 3 criteria: T4 lymphocytes < 50/μ:L; WHO activity index 3 or 4; pre-existing AIDS-defining opportunistic infection. Normal-risk patients received 4 to 6 cycles of CHOP chemotherapy; those that achieved complete remission (CR) received zidovudine (500 mg/d) and interferon-α maintenance therapy (5 million units three times a week) for one year. High-risk patients received low-dose CHOP or vincristine/prednisone chemotherapy. Supportive care was performed with pentamidine inhalation and G-CSF. Intrathecal (it) methotrexate was given for CNS prophylaxis.The median survival was 634 days for 38 patients of the normal-risk group and 129 days for 30 patients of the high-risk group. 18 high-risk patients treated with low-dose CHOP had better survival (156 days) than 12 patients treated with vincristine/...

Regulated plasma levels of colony‐stimulating factors, interleukin‐6 and interleukin‐10 in patients with acute leukaemia and non‐Hodgkin's lymphoma undergoing cytoreductive chemotherapy

Endogenous plasma levels of granulocyte colony stimulating factor (G‐CSF), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), IL‐6 and IL‐10 were measured in a total of 70 patients undergoing cytoreductive chemotherapy for treatment of acute leukaemia or non‐Hodgkin’s lymphomas. The diagnoses were acute myeloid leukaemia (AML; n = 30), acute lymphoblastic leukaemia (ALL; n = 6), non‐Hodgkin’s lymphomas (NHL; n = 11) and other malignant haematological disorders including myelodysplastic syndromes (n = 23). After chemotherapy, plasma G‐CSF was elevated (mean 5.6 ng/ml; range 1.2–10 ng/ml), and was inversely correlated with white blood cell counts (WBC) (r = −0.7, P < 0.001). Occurrence of fever (T>38.0°C) during severe myelosuppression (WBC<1 × 109/l) was associated with an additional increase of G‐CSF levels (P < 0.001). Plasma IL‐6 correlated significantly with fever (range <1 to 1100 pg/ml, mean 130 pg/ml; r = 0.5, P < 0.001) but revealed only a weak association with WBC or platelet counts. In patients treated with recombinant G‐CSF (n = 9), an association between IL‐6 and fever was still observed after chemotherapy. During the nonfebrile status (total n = 242; AML n = 124), IL‐6 levels remained <9 pg/ml in 90% of cases, whereas G‐CSF increased with leucopenia (r = −0.72; P < 0.001). In contrast, endogenous GM‐CSF remained normal and IL‐10 showed only a slight increase (21% of samples; maximum 22 pg/ml) in severe leucopenia. In particular, IL‐10 levels did not correlate with G‐CSF or IL‐6 levels.

Liposomal 1,25 (OH)2 vitamin D3 compounds block proliferation and induce differentiation in myelomonocytic leukaemia cells.

The vitamin D3 derived hormone 1,25 (OH)2 vitamin D3 (1,25 D3) is able to induce growth arrest and differentiation in myelomonocytic leukaemia cells. In order to allow for specific delivery to leukaemic cells the lipophilic compound was incorporated into the lipid membranes of liposomes. Liposomal 1,25 D3 reduced proliferation as measured by 3H‐thymidine incorporation in HL60 leukaemia cells by up to 60%. When liposomes were prepared at different concentrations of 1,25 D3 65% inhibition was achieved at 48 nM. The MC 1288 stereoisomer of 1,25 D3 was more potent and had the same activity at 48 nM.

The CD19+ B‐cell counts at peripheral blood stem cell mobilization determine different levels of tumour contamination and autograft purgability in low‐grade lymphoma

Summary. The tumour load of peripheral blood stem cell (PBSC) harvests and the outcome of ex vivo immunomagnetic B‐cell purging was investigated in 19 patients with low‐grade lymphoma. To quantify the tumour load, we combined fluorescence‐activated cell sorting measurement of CD19+ B‐cells and determination of the B‐cell light chain ratio (LCR) with consensus complementarity‐determining region III‐polymerase chain reaction (CDRIII‐PCR) and gene scan analysis. The number of tumour cells was calculated using B‐cell extracts from the PBSCs. Two different patterns were distinguished. In eight patients (42%) with CD19+ B cells > 1% in the apheresis product, a high tumour load was found, characterized by a monoclonal LCR, positive PCR in seven out of eight cases, > 5 × 107 extracted lymphoma cells in six out of seven PCR‐assessable cases, and the presence of residual lymphoma after purging in six of seven cases. In 11 patients (58%) with < 1% CD19+ B‐cells in the product, a low tumour load was indicated by a polyclonal LCR, positive PCR in only 4 out of 11 cases, > 5 × 107 extracted lymphoma cells in zero out of four PCR‐assessable cases, and the presence of residual lymphoma after purging in zero out of four of these cases. The level of residual lymphoma following purging largely depended on the level of tumour contamination. CD19+ B‐cells > 50/µl in the peripheral blood at mobilization predicted a high tumour load in the apheresis product.